Project Summary Harmful compounds and xenobiotics carried in inhaled air continually assault the nasal cavity and can cause severe nasal inflammation. Worldwide, hundreds of millions of adults and children suffer with asthma, rhinosinusitis, and other respiratory conditions. Environmental irritants and bacterial infections can trigger these types of nasal inflammation. In the nasal passages, the detection of inflammation triggers is mostly mediated by the trigeminal chemosensory system and the solitary chemosensory cells (SCCs). Known ligands of the SCCs are the bitter compound denatonium benzoate, used in several household products, and acyl homoserine lactones (AHLs) generated by bacterial infections. SCCs, which express elements of the bitter taste (T2R) transduction cascade, are innervated by trigeminal nerve fibers, which relay their responses to the central nervous system, triggering release of neuropeptides into the mucosa, evoking inflammatory/immune responses and respiratory-protective reflexes to eliminate the irritating compounds. Denatonium and AHLs are prototypical compounds for the activation of the T2R pathway in SCCs. Thus, studying their effects on SCCs can increase our understanding of airway chemoreception and of long-term effects of exposure to SCC triggers. In this proposed research, we will determine whether SCC activation by denatonium and bacterial AHLs triggers avoidance behavior, preventing further inhalation of these irritants (Aim 1); whether the presence of denatonium triggers the same nasal inflammation and immune response as bacterial infections (Aim 2); and whether forced exposure to denatonium or AHLs can damage the olfactory epithelium and if SCCs are protective in these circumstances (Aim 3). Because social, work, and other situations often require people to ignore physiological warnings triggered by SCCs and stay in environments where irritating and toxic compounds are present, it is important to understand how SCCs function and to determine the chemosensory mechanisms and the physiological/behavioral effects of commonly encountered irritant compounds like denatonium. Understanding the transduction cascades and mechanisms involved in these responses will offer new selective pharmacological targets for several airway pathologies.